title: The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands.
abstract: Voltage-gated potassium (Kv) channels derive their voltage sensitivity from movement of gating charges in voltage-sensor domains (VSDs). The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kv1.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and electrophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel activators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Zhuxi
authors.initials: Z
authors.lastname: Chen
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Sun
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Gao
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004827:Epilepsy / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology; D051658:KCNQ2 Potassium Channel / Q000819:agonists / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D051637:Shaker Superfamily of Potassium Channels / Q000378:metabolism*; D055672:Static Electricity
chemical_list: D000927:Anticonvulsants; D001549:Benzamides; D051658:KCNQ2 Potassium Channel; C587501:N-(6-chloropyridin-3-yl)-4-fluorobenzamide; D011725:Pyridines; D051637:Shaker Superfamily of Potassium Channels